From Beyond The Rainbow Somewhere

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Amyloid beta plaques (brown), a hallmark of Alzheimer’s disease, in the cerebral cortex.

A new study by Harvard Medical School researchers at Massachusetts General Hospital reveals how amyloid beta, the protein deposited into plaques in the brains of patients with Alzheimer’s disease, protects the brain from the effects of herpes viruses.

Along with another study appearing in the same July 11 issue of Neuron, which found elevated levels of three types of herpesvirus in the brains of patients with Alzheimer’s disease, the HMS team’s results support a potential role for viral infection in accelerating amyloid beta deposition and Alzheimer’s progression.

“There have been multiple epidemiological studies suggesting people with herpes infections are at higher risk for Alzheimer’s disease, along with the most recent findings from Icahn School of Medicine at Mt. Sinai that are being published with our study,” said corresponding author Rudolph Tanzi, the HMS Joseph P. and Rose F. Kennedy Professor of Child Neurology and Mental Retardation at Mass General.

“Our findings reveal a simple and direct mechanism by which herpes infections trigger the deposition of brain amyloid as a defense response in the brain,” Tanzi said. “In this way, we have merged the infection hypothesis and amyloid hypothesis into one ‘antimicrobial response hypothesis’ of Alzheimer’s disease.”

Previous studies led by Tanzi and co-corresponding author Robert Moir, HMS assistant professor of neurology at Mass General, found evidence indicating that amyloid beta, which has long been thought to be useless “metabolic garbage,” was an antimicrobial protein of the body’s innate immune system. Amyloid beta appears capable of protecting animal models and cultured human brain cells from dangerous infections.

Brain infection with herpes simplex, the virus that causes cold sores, is known to increase with aging, leading to almost universal presence of that and other herpes strains in the brain by adulthood. The HMS team set out to find whether amyloid beta could protect against herpes infection and, if so, the mechanism by which such protection takes place.

After first finding that transgenic mice engineered to express human amyloid beta survive significantly longer after injections of herpes simplex into their brains than do nontransgenic mice, the researchers found that amyloid beta inhibited infection of cultured human brain cells with herpes simplex and two other herpes strains by binding to proteins on the viral membranes and clumping into fibrils that entrap the virus and prevent it from entering cells.

Amyloid beta plaques

Further experiments with the transgenic mice revealed that introduction of herpes simplex into the brains of 5- to 6-week-old animals induced rapid development of amyloid beta plaques, which usually appear only when the animals are 10 to 12 weeks old.

“Our findings show that amyloid entrapment of herpesviruses provides immediate, effective protection from infection,” Moir said. “But it’s possible that chronic infection with pathogens like herpes that remain present throughout life could lead to sustained and damaging activation of the amyloid-based immune response, triggering the brain inflammation that drives a cascade of pathologies leading to the onset of Alzheimer’s disease.”

“A key insight is that it’s not direct killing of brain cells by herpes that causes Alzheimer’s, rather, it’s the immune response to the virus that leads to brain-damaging neuroinflammation,” Moir said.

“Our data and the Mt. Sinai findings suggest that an antimicrobial protection model utilizing both anti-herpes and anti-amyloid drugs could be effective against early Alzheimer’s disease,” he added. “Later on, when neuroinflammation has begun, greater benefit may come from targeting inflammatory molecules. However, it remains unclear whether infection is the disease’s root cause. After all, Alzheimer’s is a highly heterogeneous disease, so multiple factors may be involved in its development.”

“We are currently conducting what we call the ‘brain microbiome project,’ to characterize the population of microbes normally found in the brain,” said Tanzi, who is director of the Genetics and Aging Research Unit in the MassGeneral Institute for Neurodegenerative Disease. “The brain used to be considered sterile, but it turns out to have a resident population of microbes, some of which may be needed for normal brain health.”

“Our preliminary findings suggest that the brain microbiome is severely disturbed in Alzheimer’s disease and that bad players, including herpes viruses, seem to take advantage of the situation, leading to trouble for the patient,” Tanzi said. “We are exploring whether Alzheimer’s pathogenesis parallels the disrupted microbiome models seen in conditions like inflammatory bowel disease, and the data generated to date are both surprising and fascinating.”

Building a World

Our raw sensory experiences — what we see, hear, feel, taste, and smell — make up our construction the world around us. But how? How does this continuous stream of raw data translate into a seamless understanding of our existence?

One of the two studies, which was published on Jan. 30 in the journal Neuron, reveals how signals that arrive through different channels (from different senses) integrate in this brain region. In this study, researchers wanted to know how we recognize objects without all of its sensory properties. In other words, they wondered how, once we’ve experienced something like an apple, we’re able to know what it is by sight alone (without smelling, tasting, or feeling it).

They explored this by measuring neural activity in the PPCs of trained rats as they interacted with objects. The researchers found that, while neurons varied in how they encoded objects, the neural response was the same for touch, vision, and audition.

“This means that the message of the neurons was the object itself, not the sensory modality through which the object was explored,” Mathew Diamond, senior investigator, said in a press release.

Exploring Senses

In the second paper, published Friday, Jan. 9, in the journal Nature, researchers zeroed in on the exact neural circuit in the PPC that can sometime cause our expectations to actually taint our memories. They examined how recent sensory memories are both formed and kept by training rats to compare the volume of two separated sounds of different volumes — testing them over and over again.

By observing the rats’ PPCs, the researchers found that, as the rodents waited for the second sound, the memory of the latest sound they heard shifted towards the average of all the previous sounds from their previous tests. The results confirmed that PPC can cause memory to slide towards the expected value.

How does the brain make sense of sensory stimuli like sound?

These results still have to be replicated in human brains before we can apply the findings to ourselves. But, the deeper we explore into how and why the brain functions as it does, even in model animals like rats, the more insights we can gain to better we understand the human species.

For decades upon decades, scientists have wondered how the raw sensory data that barrages our brains every day shapes our perception of the world. These studies suggest that the PPC takes part in two critical processes: the integration of sensory signals and the storage a retrieval of stimulus memory. They also indicate that three senses — seeing, hearing, and touch feeling — are integrated in the PPC.

We’re not wired to feel safe all the time, but maybe one day we could be.

A new study investigating the neurological basis of anxiety in the brain has identified ‘anxiety cells’ located in the hippocampus – which not only regulate anxious behaviour but can be controlled by a beam of light.

The findings, so far demonstrated in experiments with lab mice, could offer a ray of hope for the millions of people worldwide who experience anxiety disorders (including almost one in five adults in the US), by leading to new drugs that silence these anxiety-controlling neurons.

“We wanted to understand where the emotional information that goes into the feeling of anxiety is encoded within the brain,” says one of the researchers, neuroscientist Mazen Kheirbek from the University of California, San Francisco.

To find out, the team used a technique called calcium imaging, inserting miniature microscopes into the brains of lab mice to record the activity of cells in the hippocampus as the animals made their way around their enclosures.

Anxiety cells (Hen Lab/Columbia University)

These weren’t just any ordinary cages, either.

The team had built special mazes where some paths led to open spaces and elevated platforms – exposed environments known to induce anxiety in mice, due to increased vulnerability to predators.

Away from the safety of walls, something went off in the mice’s heads – with the researchers observing cells in a part of the hippocampus called ventral CA1 (vCA1) firing up, and the more anxious the mice behaved, the greater the neuron activity became.

“We call these anxiety cells because they only fire when the animals are in places that are innately frightening to them,” explains senior researcher Rene Hen from Columbia University.

The output of these cells was traced to the hypothalamus, a region of the brain that – among other things – regulates the hormones that controls emotions.

Because this same regulation process operates in people, too – not just lab mice exposed to anxiety-inducing labyrinths – the researchers hypothesise that the anxiety neurons themselves could be a part of human biology, too.

“Now that we’ve found these cells in the hippocampus, it opens up new areas for exploring treatment ideas that we didn’t know existed before,” says one of the team, Jessica Jimenez from Columbia University’s Vagelos College of Physicians & Surgeons.

Even more exciting is that we’ve already figured out a way of controlling these anxiety cells – in mice at least – to the extent it actually changes the animals’ observable behaviour.

Using a technique called optogenetics to shine a beam of light onto the cells in the vCA1 region, the researchers were able to effectively silence the anxiety cells and prompt confident, anxiety-free activity in the mice.

“If we turn down this activity, will the animals become less anxious?” Kheirbek told NPR.

“What we found was that they did become less anxious. They actually tended to want to explore the open arms of the maze even more.”

This control switch didn’t just work one way.

By changing the light settings, the researchers were also able to enhance the activity of the anxiety cells, making the animals quiver even when safely ensconced in enclosed, walled surroundings – not that the team necessarily thinks vCA1 is the only brain region involved here.

“These cells are probably just one part of an extended circuit by which the animal learns about anxiety-related information,” Kheirbek told NPR, highlighting other neural cells justify additional study too.

In any case, the next steps will be to find out whether the same control switch is what regulates human anxiety – and based on what we know about the brain similarities with mice, it seems plausible.

If that pans out, these results could open a big new research lead into ways to treat various anxiety conditions.

And that’s something we should all be grateful for.

“We have a target,” Kheirbek explained to The Mercury News. “A very early way to think about new drugs.”

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A normal mouse neuron with intact docking stations (in green). Docking stations, critical parts of a neuron’s communication machinery, house neurotransmitter-packed bubbles (in red) that stand ready to launch when a trigger arrives. A new HMS study reveals that even when these docking stations are dismantled, neurons retain some of their ability to communicate with each other.

Neuroscientists have long known that brain cells communicate with each other through the release of tiny bubbles packed with neurotransmitters—a fleet of vessels docked along neuronal ends ready to launch when a trigger arrives.

Now, a study conducted in mice by neurobiologists at Harvard Medical School reveals that dismantling the docking stations that house these signal-carrying vessels does not fully disrupt signal transmission between cells.

The team’s experiments, described Aug. 17 in the journal Neuron, suggest the presence of mechanisms that help maintain partial communication despite serious structural aberrations.

“Our results not only address one of the most fundamental questions about neuronal activity and the way cells in the brain communicate with each other but uncover a few surprises too,” said Pascal Kaeser, senior author on the study and assistant professor of neurobiology at HMS.

“Our findings point to a fascinating underlying resilience in the nervous system.”

Ultrafast signal transmission between neurons is vital for normal neurologic and cognitive function. In the brain, cell-to-cell communication occurs at the junction that connects two neurons—a structure known as a synapse.

At any given moment, neurotransmitter-carrying vesicles are on standby at designated docking stations, called active zones, each awaiting a trigger to release its load across the synaptic cleft and deliver it to the next neuron.

Signal strength and speed are determined by the number of vesicles ready and capable of releasing their cargo to the next neuron.

Neuroscientists have thus far surmised that destroying the docking stations that house neurotransmitter-loaded bubbles would cause all cell-to-cell communication to cease. The HMS team’s findings suggest otherwise.

“Neurons appear to retain some residual communication even with a key piece of their communication apparatus missing.” – Shan Shan Wang

To examine the relationship between docking stations and signal transmission, researchers analyzed brain cells from mice genetically altered to lack two key building proteins, the absence of which led to the dismantling of the entire docking station.

When researchers measured signal strength in neurons with missing docking stations, they observed that those cells emitted much weaker signals when demand to transmit information was low. However, when stronger triggers were present, these cells transmitted remarkably robust signals, the researchers noticed.

“We would have guessed that signal transmission would cease altogether but it didn’t,” said Shan Shan Wang, a neuroscience graduate student in Kaeser’s lab and a co-first author of the study. “Neurons appear to retain some residual communication even with a key piece of their communication apparatus missing.”

Elimination of one active zone building block, a protein called RIM, led to a three-quarter reduction in the pool of vesicles ready for release. Disruption of another key structural protein, ELKS, resulted in one-third fewer ready-to-deploy vesicles. When both proteins were missing, however, the total reduction in the number of releasable vesicles was far less than expected. More than 40 percent of a neuron’s vesicles remained in a “ready to launch” state even with the entire docking station broken down and vesicles failing to dock.

The finding suggests that not all launch-ready vesicles need to be docked in the active zone when a trigger arrives. Neurons, the researchers say, appear to form a remote critical reserve of vesicles that can be quickly marshaled in times of high demand.

“In the absence of a docking sites, we observed that vesicles could be quickly recruited from afar when the need arises,” said Richard Held, an HMS graduate student in neuroscience and co-first author on the paper.

The team cautions that any clinical implications remain far off, but say that their observations may help explain how defects in genes responsible for making neuronal docking stations may be implicated in a range of neurodevelopmental disorders.

A single neuron in a normal adult brain likely has more than a thousand genetic mutations that are not present in the cells that surround it, according to new research. The majority of these mutations appear to arise while genes are in active use, after brain development is complete.

Active neuron illustration (stock image). Researchers have found that every neuron’s genome was unique. Each had more than 1,000 point mutations (mutations that alter a single letter of the genetic code), and only a few mutations appeared in more than one cell.

A single neuron in a normal adult brain likely has more than a thousand genetic mutations that are not present in the cells that surround it, according to new research from Howard Hughes Medical Institute (HHMI) scientists. The majority of these mutations appear to arise while genes are in active use, after brain development is complete.

“We found that the genes that the brain uses most of all are the genes that are most fragile and most likely to be mutated,” says Christopher Walsh, an HHMI investigator at Boston Children’s Hospital who led the research. Walsh, Peter Park, a computational biologist at Harvard Medical School, and their colleagues reported their findings in the October 2, 2015, issue of the journalScience.

It’s not yet clear how these naturally occurring mutations impact the function of a normal brain, or to what extent they contribute to disease. But by tracing the distribution of mutations among cells, Walsh and his colleagues are already learning new information about how the human brain develops. “The genome of a single neuron is like an archeological record of that cell,” Walsh says. “We can read its lineage in the pattern of shared mutations. We now know that if we examined enough cells in enough brains, we could deconstruct the whole pattern of development of the human brain.”

Cells of many shapes, sizes, and function are intimately intertwined inside the brain, and scientists have wondered for centuries how that diversity is generated. Scientists are further interested in genome variability between neurons due to evidence from Walsh’s lab and others that mutations that affect only a small fraction of cells in the brain can cause serious neurological disease. Until recently, however, scientists who wanted to explore that diversity were stymied by the scant amount of DNA inside neurons: Although researchers could isolate the genetic material from an individual neuron, there was simply not enough DNA to sequence, so cell-to-cell comparisons were impossible.

Walsh’s team undertook its current study thanks to technology that has become available in the last few years for amplifying the full genomes of individual cells. With plenty of DNA now available, the scientists could fully sequence an individual neuron’s genome and scour it for places where that cell’s genetic code differed from that of other cells.

The scientists isolated and sequenced the genomes of 36 neurons from healthy brains donated by three adults after their deaths. For comparison, the scientists also sequenced DNA that they isolated from cells in each individual’s heart. That effort yielded mountains of data, and Walsh’s group teamed up with Park and Semin Lee, a postdoctoral fellow in Park’s group, to make sense of it all.

What they found was that every neuron’s genome was unique. Each had more than 1,000 point mutations (mutations that alter a single letter of the genetic code), and only a few mutations appeared in more than one cell. What’s more, the nature of the variation was not quite what the scientists had expected.

“We expected these mutations to look like cancer mutations,” Walsh says, explaining that cancer mutations tend to arise when DNA is imperfectly copied in preparation for cell division, “but in fact they have a unique signature all their own. The mutations that occur in the brain mostly seem to occur when the cells are expressing their genes.”

Neurons don’t divide, and most of the time their DNA is tightly bundled and protected from damage. When a cell needs to turn on a gene, it opens up the DNA, exposing the gene so that it can be copied into RNA, the first step in protein production. Based on the types and locations of the mutations they found in the neurons, the scientists concluded that most DNA damage had occurred during this unwinding and copying process.

While most of the mutations in the neurons were unique, a small percentage did turn up in more than one cell. That signaled that those mutations had originated when future brain cells were still dividing, a process that is complete before birth. Those early mutations were passed on as cells divided and migrated, and the scientists were able to use them to reconstruct a partial history of the brain’s development.

“We knew that cells that shared a certain mutation were related, so we could look at how different cells in the adult were related to each other during development,” explains Mollie Woodworth, a postdoctoral researcher in Walsh’s lab. Their mapping revealed that closely relatedly cells could wind up quite distant from one another in the adult brain. A single patch of brain tissue might contain cells from five different lineages that diverged before the developing brain had even separated from other tissues in the fetus. “We could identify mutations that happened really early, before the brain existed, and we found that cells that had those mutations were nestled next to cells that had totally different mutations,” Woodworth says. In fact, the scientists found, a particular neuron might be more closely related to a cell in the heart than to a neighboring neuron.

The scientists say intermingling cells with different developmental origins might protect the brain from the effects of early-arising, potentially harmful mutations. Although most of the mutations the scientists catalogued were harmless, they did encounter mutations that disrupted genes that, when impaired throughout the brain, can cause disease. “By having very mixed populations, cells that are next to each other and responsible for a similar task are not very closely related to each other, so they’re not likely to share the same deleterious mutation,” says Michael Lodato, who is also a postdoctoral researcher in Walsh’s lab. That could reduce the risk of a particular mutation interfering with a localized brain function, he explains.

Still, the scientists say, this abundance of mutations could influence the function of a normal brain. “To what extent do these clonal mutations normally shape the development of the brain, in a negative way or a positive way?” says Walsh. “To what extent do we have a patch of brain that doesn’t work quite right, but not so much that we would call it a disease? That’s a big open question.”

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Scientists at The Scripps Research Institute (TSRI) have identified a molecule in the brain that triggers schizophrenia-like behaviors, brain changes and global gene expression in an animal model. The research gives scientists new tools for someday preventing or treating psychiatric disorders such as schizophrenia, bipolar disorder and autism.

“This new model speaks to how schizophrenia could arise before birth and identifies possible novel drug targets,” said Jerold Chun, a professor and member of the Dorris Neuroscience Center at TSRI who was senior author of the new study.

The findings were published April 7, 2014, in the journal Translational Psychiatry.

What Causes Schizophrenia?

According to the World Health Organization, more than 21 million people worldwide suffer from schizophrenia, a severe psychiatric disorder that can cause delusions and hallucinations and lead to increased risk of suicide.

Although psychiatric disorders have a genetic component, it is known that environmental factors also contribute to disease risk. There is an especially strong link between psychiatric disorders and complications during gestation or birth, such as prenatal bleeding, low oxygen or malnutrition of the mother during pregnancy.

In the new study, the researchers studied one particular known risk factor: bleeding in the brain, called fetal cerebral hemorrhage, which can occur in utero and in premature babies and can be detected via ultrasound.

In particular, the researchers wanted to examine the role of a lipid called lysophosphatidic acid (LPA), which is produced during hemorrhaging. Previous studies had linked increased LPA signaling to alterations in architecture of the fetal brain and the initiation of hydrocephalus (an accumulation of brain fluid that distorts the brain). Both types of events can also increase the risk of psychiatric disorders.

“LPA may be the common factor,” said Beth Thomas, an associate professor at TSRI and co-author of the new study.

Mouse Models Show Symptoms

To test this theory, the research team designed an experiment to see if increased LPA signaling led to schizophrenia-like symptoms in animal models.

Hope Mirendil, an alumna of the TSRI graduate program and first author of the new study, spearheaded the effort to develop the first-ever animal model of fetal cerebral hemorrhage. In a clever experimental paradigm, fetal mice received an injection of a non-reactive saline solution, blood serum (which naturally contains LPA in addition to other molecules) or pure LPA.

Ten weeks after the mice were born, they were tested for schizophrenia-like symptoms. The researchers found that female mice given LPA-containing serum or LPA alone displayed hyperactivity upon stimulation, showed anxiety and had increased numbers of dopamine-producing neurons—all which are characteristic of schizophrenia and other psychiatric disorders.

The real litmus test to show if these symptoms were specific to psychiatric disorders, according to Mirendil, was “prepulse inhibition test,” which measures the “startle” response to loud noises. Most mice—and humans—startle when they hear a loud noise. However, if a softer noise (known as a prepulse) is played before the loud tone, mice and humans are “primed” and startle less at the second, louder noise. Yet mice and humans with symptoms of schizophrenia startle just as much at loud noises even with a prepulse, perhaps because they lack the ability to filter sensory information.

Indeed, the female mice injected with serum or LPA alone startled regardless of whether a prepulse was placed before the loud tone.

Next, the researchers analyzed brain changes, revealing schizophrenia-like changes in neurotransmitter-expressing cells. Global gene expression studies found that the LPA-treated mice shared many similar molecular markers as those found in humans with schizophrenia. To further test the role of LPA, the researchers used a molecule to block only LPA signaling in the brain.

This treatment prevented schizophrenia-like symptoms.

Implications for Human Health

This research provides new insights, but also new questions, into the developmental origins of psychiatric disorders.

For example, the researchers only saw symptoms in female mice. Could schizophrenia be triggered by different factors in men and women as well?

“Hopefully this animal model can be further explored to tease out potential differences in the pathological triggers that lead to disease symptoms in males versus females,” said Thomas.

In addition to Chun, Thomas and Mirendil, authors of the study, “LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage,” were Candy De Loera of TSRI; and Kinya Okada and Yuji Inomata of the Mitsubishi Tanabe Pharma Corporation.

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According to survey data from the Centers for Disease Control and Prevention released today (March 27), one in 68 eight-year-olds in the U.S. has an autism spectrum disorder. That’s nearly double what was estimated a decade ago. It’s not entirely clear why, but researchers are getting closer and closer to understanding the neural roots of autism. In a study published today in the New England Journal of Medicine, researchers from the University of California, San Diego, and their colleagues examined the brains of 22 children who died. The team found that kids who had autism were far more likely to have had disorganized patches of cortical neurons than those who didn’t have the disorder.
Given that the cortex takes shape prenatally, the researchers interpreted their findings as a sign that the brain changes leading to autism begin in utero. “If this new report of disorganized architecture in the brains of some children with autism is replicated, we can presume this reflects a process occurring long before birth,” Thomas Insel, the director of National Institute of Mental Health, which funded the research, said in a statement. “This reinforces the importance of early identification and intervention.”

The cortex is normally ordered in distinct layers of neurons, but 91 percent of the autistic children had small regions in their brains where genetic markers of these layers were absent. In comparison, just 9 percent of the kids without autism had these regions of disorganization. The patches were about five to seven millimeters in length and spanned several layers of cortical neurons. “The most surprising finding was the similar early developmental pathology across nearly all of the autistic brains, especially given the diversity of symptoms in patients with autism,” coauthor Ed Lein of the Allen Institute for Brain Science in Seattle said in a press release.
Stanley Nelson, a geneticist at UCLA, told NPR that the results add to the evidence that autism begins before birth. “The overwhelming set of data is that the problems are existing during brain development, probably as an embryo or fetus,” he said.

The men were having a routine procedure to locate regions in their brains that caused epileptic seizures when they felt their heart rates rise, a sense of foreboding, and an overwhelming desire to persevere against a looming hardship.

The remarkable findings could help researchers develop treatments fordepression and other disorders where people are debilitated by a lack of motivation.

One patient said the feeling was like driving a car into a raging storm. When his brain was stimulated, he sensed a shaking in his chest and a surge in his pulse. In six trials, he felt the same sensations time and again.

Comparing the feelings to a frantic drive towards a storm, the patient said: “You’re only halfway there and you have no other way to turn around and go back, you have to keep going forward.”

When asked by doctors to elaborate on whether the feeling was good or bad, he said: “It was more of a positive thing, like push harder, push harder, push harder to try and get through this.”

A second patient had similar feelings when his brain was stimulated in the same region, called the anterior midcingulate cortex (aMCC). He felt worried that something terrible was about to happen, but knew he had to fight and not give up, according to a case study in the journal Neuron.

Both men were having an exploratory procedure to find the focal point in their brains that caused them to suffer epileptic fits. In the procedure, doctors sink fine electrodes deep into different parts of the brain and stimulate them with tiny electrical currents until the patient senses the “aura” that precedes a seizure. Often, seizures can be treated by removing tissue from this part of the brain.

“In the very first patient this was something very unexpected, and we didn’t report it,” said Josef Parvizi at Stanford University in California. But then I was doing functional mapping on the second patient and he suddenly experienced a very similar thing.”

“Its extraordinary that two individuals with very different past experiences respond in a similar way to one or two seconds of very low intensity electricity delivered to the same area of their brain. These patients are normal individuals, they have their IQ, they have their jobs. We are not reporting these findings in sick brains,” Parvizi said.

The men were stimulated with between two and eight milliamps of electrical current, but in tests the doctors administered sham stimulation too. In the sham tests, they told the patients they were about to stimulate the brain, but had switched off the electical supply. In these cases, the men reported no changes to their feelings. The sensation was only induced in a small area of the brain, and vanished when doctors implanted electrodes just five millimetres away.

Parvizi said a crucial follow-up experiment will be to test whether stimulation of the brain region really makes people more determined, or simply creates the sensation of perseverance. If future studies replicate the findings, stimulation of the brain region – perhaps without the need for brain-penetrating electrodes – could be used to help people with severe depression.

The anterior midcingulate cortex seems to be important in helping us select responses and make decisions in light of the feedback we get. Brent Vogt, a neurobiologist at Boston University, said patients with chronic pain and obsessive-compulsive disorder have already been treated by destroying part of the aMCC. “Why not stimulate it? If this would enhance relieving depression, for example, let’s go,” he said.

Nicotine withdrawal might take over your body, but it doesn’t take over your brain. The symptoms of nicotine withdrawal are driven by a very specific group of neurons within a very specific brain region, according to a report in Current Biology, a Cell Press publication, on November 14. Although caution is warranted, the researchers say, the findings in mice suggest that therapies directed at this group of neurons might one day help people quit smoking.

“We were surprised to find that one population of neurons within a single brain region could actually control physical nicotine withdrawal behaviors,” says Andrew Tapper of the Brudnick Neuropsychiatric Research Institute at the University of Massachusetts Medical School.

Tapper and his colleagues first obtained mice addicted to nicotine by delivering the drug to mice in their water for a period of 6 weeks. Then they took the nicotine away. The mice started scratching and shaking in the way a dog does when it is wet. Close examination of the animals’ brains revealed abnormally increased activity in neurons within a single region known as the interpeduncular nucleus.

When the researchers artificially activated those neurons with light, animals showed behaviors that looked like nicotine withdrawal, whether they had been exposed to the drug or not. The reverse was also true: treatments that lowered activity in those neurons alleviated nicotine withdrawal symptoms.

That the interpeduncular nucleus might play such a role in withdrawal from nicotine makes sense because the region receives connections from other areas of the brain involved in nicotine use and response, as well as feelings of anxiety. The interpeduncular nucleus is also densely packed with nicotinic acetylcholine receptors that are the molecular targets of nicotine.

It is much less clear whether the findings related to nicotine will be relevant to other forms of addiction, but there are some hints that they may.

“Smoking is highly prevalent in people with other substance-use disorders, suggesting a potential interaction between nicotine and other drugs of abuse,” Tapper says. “In addition, naturally occurring mutations in genes encoding the nicotinic receptor subunits that are found in the interpeduncular nucleus have been associated with drug and alcohol dependence.”